Sparsentan: The Dual Endothelin and Angiotensin Blocker for IgA Nephropathy and Focal Segmental Glomerulosclerosis

Sparsentan is a kidney medicine taken as a tablet once a day. It is a single molecule that blocks two hormone receptors at once: the endothelin type A receptor and the angiotensin II type 1 receptor. Both hormones narrow blood vessels and, inside the kidney, both are linked to scarring and to the leak of protein from the kidney's filters into the urine. In the United States sparsentan is approved for two kidney diseases: immunoglobulin A (IgA) nephropathy, in which deposits of the antibody immunoglobulin A inflame the kidney's filters, and focal segmental glomerulosclerosis, a pattern of scarring in the filters that often leaks large amounts of protein. This page sets out how the drug works, how its approvals came about, what the main trials found, what the label warns about, and what is still unknown. The diseases themselves are covered on the IgA nephropathy and focal segmental glomerulosclerosis pages.

Table of Contents

  1. How Blocking Two Receptors Lowers Urine Protein
  2. The United States Approval History
  3. PROTECT: Sparsentan Against Irbesartan in IgA Nephropathy
  4. Later IgA Nephropathy Studies
  5. DUET: The First Trial in Focal Segmental Glomerulosclerosis
  6. DUPLEX: Protein Fell, Kidney Function Did Not Differ
  7. The Focal Segmental Glomerulosclerosis Label and the Nephrotic Split
  8. The Boxed Warning: Liver Injury and Harm to an Unborn Baby
  9. Side Effects Reported in the Trials
  10. Dosing and Drug Interactions in the Label
  11. What Is Not Known
  12. Key Research Papers
  13. Connections
  14. Featured Videos

How Blocking Two Receptors Lowers Urine Protein

Each kidney holds a very large number of tiny filters called glomeruli. A healthy filter lets water and waste through and holds protein back in the blood. In IgA nephropathy and in focal segmental glomerulosclerosis the filters are damaged, protein leaks into the urine (proteinuria), and studies of both diseases link a lower protein leak with a slower loss of kidney function (Heerspink 2026; Trachtman 2023).

Two hormones are central to this story. Angiotensin II is the hormone that older kidney drugs such as angiotensin receptor blockers already target. Endothelin-1 is a second, separate vessel-narrowing hormone made inside the kidney. The US prescribing information states that endothelin-1 and angiotensin II are thought to be involved in the disease process of both IgA nephropathy and focal segmental glomerulosclerosis, acting through the endothelin type A receptor and the angiotensin II type 1 receptor respectively. Sparsentan blocks both of those receptors with one molecule.

The label gives the drug's binding strength: a high affinity for both the endothelin type A receptor (Ki 12.8 nM) and the angiotensin II type 1 receptor (Ki 0.36 nM), where Ki is the inhibition constant and a lower number means tighter binding, with more than 500-fold selectivity for these two receptors over the endothelin type B and angiotensin II type 2 receptors. In plain terms, it grips the two targets it is meant to block and largely leaves their sister receptors alone.

Laboratory work by researchers including the drug's developers describes what this double block does in animal kidneys. A 2024 review of studies in models of chronic kidney disease summarised anti-inflammatory, anti-scarring and blood-flow effects of sparsentan in the kidney, with protective actions reported in the filter's lining cells, its supporting (mesangial) cells, the surrounding tubules and the podocytes, the specialised cells that form the final protein barrier (Kohan 2024). In a mouse model of focal segmental glomerulosclerosis, filmed inside the living kidney with a special microscope, sparsentan widened the small arteries feeding and draining the filters, reduced proteinuria, preserved podocyte numbers and restored the sugary protective coat that lines the filter's blood vessels in mice; these effects were absent or smaller with the angiotensin receptor blocker losartan (Gyarmati 2024). In gddY mice, a strain that develops a disease resembling IgA nephropathy on its own, the urine albumin level fell faster and further with sparsentan than with losartan at doses that lowered blood pressure to a similar degree in mice (Nagasawa 2024). Animal findings show possible mechanisms; they do not show that the same happens in people.

Back to Table of Contents

The United States Approval History

The approval record comes from the U.S. Food and Drug Administration's Drugs@FDA database and the approval letters it publishes for this drug's new drug application.

The label's first approval line reads "Initial U.S. Approval: 2023." The full current text is on DailyMed (US prescribing information, revised April 2026), and the approval letters are linked from Drugs@FDA, application 216403. The label lists no other uses; sparsentan is not approved in the United States for Alport syndrome or other kidney diseases.

Back to Table of Contents

PROTECT: Sparsentan Against Irbesartan in IgA Nephropathy

PROTECT was a phase 3, randomised, double-blind trial run at 134 sites in 18 countries. It enrolled adults with biopsy-proven IgA nephropathy who still leaked 1.0 g of protein a day or more despite at least 12 weeks of maximised treatment with a renin-angiotensin system blocker. Participants were assigned to sparsentan 400 mg once daily or to irbesartan 300 mg once daily. Irbesartan is an angiotensin receptor blocker, so the trial compared the double block against a full dose of the standard single block, not against a dummy pill.

The 36-week interim result. The prespecified interim analysis reported 404 participants (202 in each group). At week 36 the urine protein-to-creatinine ratio had fallen by 49.8% with sparsentan and 15.1% with irbesartan, a between-group relative reduction of 41% (p<0.0001). Treatment-emergent side effects were similar in the two groups, and there were no cases of severe swelling, heart failure, liver toxicity or swelling-related discontinuations (Heerspink 2023). The US label reports this same interim analysis using the first 281 patients who had reached week 36: a 45% fall with sparsentan against a 15% fall with irbesartan, a 35% reduction in the ratio of mean values (95% confidence interval 23% to 45%). The two figures come from different patient sets and analysis methods; both point the same way.

The two-year kidney function result. The final double-blind analysis followed patients for 110 weeks (Rovin 2023). Kidney function was tracked as the estimated glomerular filtration rate, a calculated measure of how much blood the kidneys clean each minute.

The US label presents its own analysis of the same 404 patients: the mean filtration rate slope from baseline to week 110 was −3.0 with sparsentan and −4.2 with irbesartan, a treatment effect of 1.2 mL/min per 1.73 m² per year (95% confidence interval 0.2 to 2.1; p=0.0168). The label's analysis counts data regardless of treatment discontinuation or the start of rescue immune-suppressing treatment, which was started in 7 patients (3%) on sparsentan and 18 (9%) on irbesartan. The label also notes that the benefit on filtration rate was not evident in the small group of patients who started with a filtration rate of 90 or above.

Back to Table of Contents

Later IgA Nephropathy Studies

Complete remission and kidney function. A post hoc analysis of PROTECT grouped patients by whether their protein leak fell below 0.3 g a day, regardless of which drug they had received. Of 404 patients, 43 (11%) reached this complete remission by week 36 and 85 (21%) at some point up to week 110. Those who reached it by week 110 lost less filtration rate (−4.0 against −8.6 mL/min per 1.73 m²), had a slower yearly decline (−0.7 against −4.2), and fewer reached the composite kidney endpoint (1% against 14%). They also had more low-blood-pressure side effects (Heerspink 2026). Because the groups were formed after the fact and mixed both treatments, this shows an association between low proteinuria and better kidney outcomes, not a separate effect of the drug.

Sparsentan as the first treatment (SPARTAN). SPARTAN gave sparsentan to 12 newly diagnosed adults who had not taken a renin-angiotensin system blocker in the previous 12 months. In the 24-week interim report, the urine protein-to-creatinine ratio fell by 61.9% at week 4 and 68.8% at week 24, and 58% of patients reached complete remission during treatment. Urine markers of inflammation and scarring also fell. Dizziness was the most frequent side effect (50% of patients) and 1 patient stopped because of low blood pressure (Cheung 2026). With 12 patients and no comparison group, this is an early signal only.

Combined with SGLT2 inhibitors. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a separate class of kidney-protecting drugs first developed for diabetes. In the open-label SPARTACUS trial, 48 patients already on a stable SGLT2 inhibitor had their renin-angiotensin system blocker replaced with sparsentan; the urine albumin-to-creatinine ratio fell by a least-squares mean of 56% through week 24. In a substudy of the PROTECT open-label extension, 63 patients on sparsentan were randomised to add an SGLT2 inhibitor or not for 12 weeks; the protein ratio was lower with the combination (ratio 0.75, 95% confidence interval 0.58 to 0.98). The authors describe the added reduction as modest and report no unexpected safety signals (Ayoub 2026).

Back to Table of Contents

DUET: The First Trial in Focal Segmental Glomerulosclerosis

DUET was a phase 2, randomised, double-blind trial in patients aged 8 to 75 with biopsy-proven focal segmental glomerulosclerosis, a filtration rate above 30 and a urine protein-to-creatinine ratio of at least 1.0 g/g. For 8 weeks, patients received sparsentan at 200, 400 or 800 mg a day or irbesartan 300 mg a day, followed by open-label sparsentan only (Trachtman 2018).

Years of follow-up. In the open-label extension, 108 patients received at least one dose of sparsentan and were followed for up to 4.6 years. Sparsentan was still being taken by 45 of 108 (41.7%) at the time of the report, and the median time to stopping was 3.9 years. Patients who reached partial remission within 9 months (52.8%) had a slower yearly fall in filtration rate than those who did not (−2.70 against −6.56; P=0.03). Swelling and low blood pressure affected 13.9% and 15.7% of patients in year 1 and 4% or fewer from year 2 on. There were no cases of heart failure and no deaths. The extension had no comparison group (Campbell 2024). A separate analysis of DUET found that 46 of 108 patients (43%) reached complete remission at least once over a median 47.0 months, and that this was associated with a slower decline in filtration rate (Trachtman 2023). A 2026 review in a journal supplement reports a 35.6% reduction in the protein ratio from baseline at 240 weeks in DUET (Bensink 2026).

Back to Table of Contents

DUPLEX: Protein Fell, Kidney Function Did Not Differ

DUPLEX was the phase 3 trial in focal segmental glomerulosclerosis. It enrolled 371 patients aged 8 to 75 with no known secondary cause of the disease: 184 were assigned to sparsentan and 187 to irbesartan for 108 weeks (Rheault 2023). The trial had two endpoints with two different results.

The authors' conclusion was that there were no significant differences in filtration rate slope at 108 weeks despite a greater reduction in proteinuria with sparsentan. The US label reports the same overall picture in a different form: an adjusted mean change in filtration rate to week 108 of −14.3 with sparsentan and −13.3 with irbesartan (difference −1.0; 95% confidence interval −4.9 to 2.8), and a protein ratio reduction of 46% against 30% at week 108. After both drugs were stopped at week 108, the label reports no difference between groups in the filtration rate or protein change at week 112.

Children and genetic disease. A post hoc look at the 35 children aged 8 to under 18 in DUPLEX (16 on sparsentan, 19 on irbesartan) found a mean protein reduction at 108 weeks of 39.5% against 24.9%, complete remission in 12.5% against 5.3%, and the partial remission endpoint in 56.3% against 36.8%, with similar side effect profiles (Rheault 2026). An exploratory analysis of patients with genetic forms of the disease identified 31 with podocyte gene variants, 25 with variants in the collagen genes COL4A3 to COL4A5 (the genes involved in Alport syndrome) and 14 with high-risk APOL1 genotypes. In these groups sparsentan produced substantial and sustained protein reductions, numerically more complete remissions, and fewer patients reaching the composite kidney endpoint than irbesartan (Yee 2026). Both are subgroup analyses that were not the trial's main question.

Back to Table of Contents

The Focal Segmental Glomerulosclerosis Label and the Nephrotic Split

The April 2026 indication covers focal segmental glomerulosclerosis without nephrotic syndrome only. Nephrotic syndrome is the severe form of protein loss in which heavy proteinuria, low blood albumin and swelling occur together. The label explains that, because the drivers of disease progression may differ in patients with and without nephrotic syndrome, DUPLEX was analysed in the two subgroups. It defines nephrotic syndrome as either a documented history of it, or the combination at baseline of proteinuria above 3.5 g in 24 hours in adults (or a protein ratio above 2.0 g/g in children), serum albumin below 3.0 g/dL, and swelling.

The label states that the drug's safety and effectiveness for this indication are established in children aged 8 and older, based on DUPLEX, which enrolled 35 children aged 9 and older, and are not established in children under 8 with focal segmental glomerulosclerosis or in any children with IgA nephropathy. A 2026 expert review notes that the absence of a definitive kidney function benefit in DUPLEX, together with the mixed population in the trial, limits firm conclusions (Juanet 2026). Another 2026 review describes how proteinuria reduction has become the preferred stand-in endpoint for trials in this disease, because the filtration rate declines at very different speeds from patient to patient (Bensink 2026).

Back to Table of Contents

The Boxed Warning: Liver Injury and Harm to an Unborn Baby

The US label carries a boxed warning, the strongest warning the U.S. Food and Drug Administration places on a prescription drug, titled "Hepatotoxicity and Embryo-Fetal Toxicity."

Liver injury. The label states that some drugs in the endothelin receptor antagonist class have caused rises in liver enzymes, liver toxicity and liver failure. In sparsentan's clinical studies, rises in the liver enzymes alanine aminotransferase (ALT) or aspartate aminotransferase (AST) to at least 3 times the upper limit of normal occurred in up to 3.5% of treated patients, including cases confirmed when the drug was restarted. The label adds that no patient in the trials had a simultaneous rise in bilirubin above 2 times the upper limit of normal, and there were no cases of liver failure. The label requires liver enzymes and bilirubin to be measured before treatment and then every 3 months, and it calls for treatment to be interrupted when enzymes rise above 3 times the upper limit of normal. It lists the symptoms it treats as signs of possible liver injury: nausea, vomiting, pain in the upper right abdomen, tiredness, loss of appetite, yellowing of the skin or eyes, dark urine, fever and itching. It instructs patients with these symptoms to stop the drug and seek medical attention. The label advises against use in people with any degree of liver impairment. The National Institutes of Health LiverTox database describes a low rate of liver enzyme rises during therapy and no linked cases of clinically apparent liver injury so far, while noting that clinical experience is limited (Hoofnagle, LiverTox).

Restricted distribution. Because of the liver risk, the drug is available in the United States only through a restricted program (a Risk Evaluation and Mitigation Strategy). Prescribers must be certified, every patient must enroll before starting and keep up with the required blood tests, and only certified pharmacies may dispense it.

Pregnancy. The drug is contraindicated in pregnancy. The label bases this on animal data: in pregnant rats given the drug during organ formation at all doses tested, there were craniofacial malformations, skeletal abnormalities, more embryo and fetal deaths, and lower fetal weights in rats; in pregnant rabbits there were maternal deaths and abortions at the higher doses. The label states that available human data for this drug class do not establish the presence or absence of fetal harm. It requires pregnancy to be excluded before starting, effective contraception before, during and for two weeks after treatment, and stopping the drug as soon as possible if pregnancy is detected. Because of the possibility of low blood pressure in a nursing infant, the label advises against breastfeeding during treatment; there are no data on whether the drug passes into human milk.

Back to Table of Contents

Side Effects Reported in the Trials

The label lists the adverse reactions reported in 2% or more of treated patients, side by side with irbesartan.

IgA nephropathy (PROTECT, 202 patients on each drug, median 110 weeks on sparsentan):

Focal segmental glomerulosclerosis (DUPLEX, 184 on sparsentan and 187 on irbesartan, median 108 weeks):

A fall in hemoglobin of more than 2 g/dL to below the normal range was more common with sparsentan (19% against 13% in PROTECT; 45% against 18% in DUPLEX). The label states that this is thought to be partly due to dilution of the blood by retained fluid, and that no patient stopped treatment because of it. Other label warnings cover low blood pressure (some cases serious), acute kidney injury, high potassium and fluid retention; the drug has not been evaluated in people with heart failure. In healthy volunteers the drug lengthened the heart's QT interval by a maximal mean of 8.8 milliseconds at 800 mg, and the label does not expect a clinically relevant effect at the approved dose.

Pooled and real-world data. A 2024 meta-analysis of three randomised trials with 884 patients found no significant differences in adverse events between sparsentan and irbesartan except low blood pressure, which was about twice as frequent with sparsentan (risk ratio 2.02) (Elnaga 2024). An analysis of 1,776 reports to the U.S. Food and Drug Administration's adverse event reporting system from 2023 to 2024 confirmed known reactions such as low blood pressure, high potassium, swelling and dizziness, and flagged possible new signals including nasopharyngitis, ear discomfort, kidney pain and chest-wall pain; the median time to onset was 18 days (Lv 2026). Spontaneous reports can raise signals but cannot show that a drug caused an event.

Back to Table of Contents

Dosing and Drug Interactions in the Label

The label gives the following doses, taken by mouth once a day before the morning or evening meal. For IgA nephropathy in adults, the label gives 200 mg for 14 days, then 400 mg as tolerated. For focal segmental glomerulosclerosis, the label gives 400 mg for 14 days, then 800 mg, for patients over 50 kg, and 200 mg for 14 days, then 400 mg, for patients of 50 kg or less. The label states that tablets may be crushed and mixed with water for people who cannot swallow them whole. The label calls for renin-angiotensin system blockers and endothelin receptor antagonists to be stopped before sparsentan begins, and the drug is contraindicated together with angiotensin receptor blockers, endothelin receptor antagonists or aliskiren, a combination the label links to low blood pressure, fainting, high potassium and kidney failure.

Sparsentan is broken down mainly by the liver enzyme cytochrome P450 3A (CYP3A). In the label's interaction studies:

The label gives a half-life of 9.6 hours at steady state, more than 99% binding to blood proteins, and about 80% of a dose leaving the body in the stool. A high-fat meal raised the peak level of an 800 mg dose by 108%.

Back to Table of Contents

What Is Not Known

Decisions about kidney medicines belong with a clinician who knows the person's full history and test results.

Back to Table of Contents

Key Research Papers

  1. Syed YY. Sparsentan: First Approval. Drugs. 2023;83(6):563-568. PubMed PMID: 37022667
  2. Heerspink HJL, Radhakrishnan J, Alpers CE, et al. Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial. Lancet. 2023;401(10388):1584-1594. PubMed PMID: 37015244
  3. Rovin BH, Barratt J, Heerspink HJL, et al. Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial. Lancet. 2023;402(10417):2077-2090. PubMed PMID: 37931634
  4. Heerspink HJL, Rovin BH, Komers R, et al. Association between Complete Proteinuria Remission and Kidney Function in the Phase 3 PROTECT Trial of Sparsentan in IgA Nephropathy. Clin J Am Soc Nephrol. 2026;21(4):578-592. PubMed PMID: 41428405
  5. Cheung CK, Barratt WA, Chaki S, et al. Sparsentan as First-Line Treatment in IgAN From SPARTAN. Kidney Int Rep. 2026;11(12):107105. PubMed PMID: 42999669
  6. Ayoub I, Alperovich G, Komers R, et al. Sparsentan - SGLT2 inhibitor combination therapy in trials of IgA nephropathy. Nephrol Dial Transplant. 2026. PubMed PMID: 42726023
  7. Trachtman H, Nelson P, Adler S, et al. DUET: A Phase 2 Study Evaluating the Efficacy and Safety of Sparsentan in Patients with FSGS. J Am Soc Nephrol. 2018;29(11):2745-2754. PubMed PMID: 30361325
  8. Campbell KN, Gesualdo L, Murphy E, et al. Sparsentan for Focal Segmental Glomerulosclerosis in the DUET Open-Label Extension: Long-term Efficacy and Safety. Kidney Med. 2024;6(6):100833. PubMed PMID: 38831932
  9. Trachtman H, Diva U, Murphy E, et al. Implications of Complete Proteinuria Remission at any Time in Focal Segmental Glomerulosclerosis: Sparsentan DUET Trial. Kidney Int Rep. 2023;8(10):2017-2028. PubMed PMID: 37850006
  10. Rheault MN, Alpers CE, Barratt J, et al. Sparsentan versus Irbesartan in Focal Segmental Glomerulosclerosis. N Engl J Med. 2023;389(26):2436-2445. PubMed PMID: 37921461
  11. Rheault MN, Dell KM, Lieberman KV, et al. Sparsentan Versus Irbesartan in Pediatric Patients With FSGS. Kidney Int Rep. 2026;11(7):106566. PubMed PMID: 42210914
  12. Yee J, Gong W, Inrig J, et al. Antiproteinuric Effect of Sparsentan in Patients with Genetic-Associated FSGS Enrolled in the DUPLEX Trial. Clin J Am Soc Nephrol. 2026;21(4):605-614. PubMed PMID: 41433094
  13. Juanet C, Soler MJ, Zand L, et al. Evaluating sparsentan for the treatment of focal segmental glomerulosclerosis. Expert Opin Pharmacother. 2026;27(13):1407-1416. PubMed PMID: 42622490
  14. Bensink ME, Gisler C, Navickas C. Review of the clinical, humanistic, and economic burden of focal segmental glomerulosclerosis. Am J Manag Care. 2026;32(7 Suppl):S126-S137. PubMed PMID: 42101820
  15. Kohan DE, Bedard PW, Jenkinson C, et al. Mechanism of protective actions of sparsentan in the kidney: lessons from studies in models of chronic kidney disease. Clin Sci (Lond). 2024;138(11):645-662. PubMed PMID: 38808486
  16. Gyarmati G, Shroff UN, Izuhara A, et al. Sparsentan improves glomerular hemodynamics, cell functions, and tissue repair in a mouse model of FSGS. JCI Insight. 2024;9(19):e177775. PubMed PMID: 39226116
  17. Nagasawa H, Ueda S, Suzuki H, et al. Sparsentan is superior to losartan in the gddY mouse model of IgA nephropathy. Nephrol Dial Transplant. 2024;39(9):1494-1503. PubMed PMID: 38271614
  18. Elnaga AAA, Alsaied MA, Elettreby AM, et al. Safety and efficacy of sparsentan versus irbesartan in focal segmental glomerulosclerosis and IgA nephropathy: a systematic review and meta-analysis of randomized controlled trials. BMC Nephrol. 2024;25(1):316. PubMed PMID: 39333921
  19. Lv T, Bao W, Chen S. Assessing the real-world safety of sparsentan for immunoglobulin A nephropathy: insights from a comprehensive analysis of FAERS database. Int Urol Nephrol. 2026;58(9):3781-3793. PubMed PMID: 41667900
  20. Hoofnagle JH. Sparsentan. In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Updated 2026 Jan 6. PubMed PMID: 41570165

PubMed Topic Searches

  1. PubMed: sparsentan in IgA nephropathy (PROTECT)
  2. PubMed: sparsentan in focal segmental glomerulosclerosis (DUPLEX)
  3. PubMed: sparsentan safety and liver effects
  4. PubMed: dual endothelin and angiotensin receptor blockade in the kidney

Back to Table of Contents

Connections

Back to Table of Contents